Submissions for variant NM_024301.5(FKRP):c.1141dup (p.Ala381fs)

dbSNP: rs754403441

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000672422	SCV000797526	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2I	2018-02-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000688076	SCV000815673	pathogenic	Walker-Warburg congenital muscular dystrophy	2024-10-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ala381Glyfs*9) in the FKRP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 115 amino acid(s) of the FKRP protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with limb girdle muscular dystrophy (PMID: 26436962). This variant is also known as c.1140_1141insG. ClinVar contains an entry for this variant (Variation ID: 556419). This variant disrupts a region of the FKRP protein in which other variant(s) (p.Ser385*) have been determined to be pathogenic (PMID: 11592034, 12666124, 12707425, 14742276). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV002282320	SCV002571193	likely pathogenic	not provided	2022-02-17	criteria provided, single submitter	clinical testing	Observed with a second FKRP variant in multiple individuals described with limb-girdle muscular dystrophy, although it is not known if the second FKRP variant is on the opposite allele (in trans) or on the same allele (in cis) (Ghaoui R et al., 2015; Song D et al., 2021); Frameshift variant predicted to result in protein truncation, as the last 115 amino acids are replaced with 8 different amino acids, and other loss-of-function variants have been reported downstream in HGMD.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27439679, 26436962, 33200426)
Baylor Genetics	RCV003459638	SCV004197445	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5	2022-11-11	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000672422	SCV002091336	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2I	2021-03-03	no assertion criteria provided	clinical testing